Delta4, 8(9)-3, 20-diketo-11, 17-dihydroxy-21-oxygenated-pregnadienes and processes of preparing the same



United rates 2,808,415 Patented Oct. 1, 1957 Lewis H. Sarett, Princeton, N. 1., assignor to Merck & Cm, lnc., Rahway, N. J., a corporation of New Hersey N Drawing. Original application January 25, 1955, Serial No. 483,853. Divided and this application Octoher 31, 1955, Serial No. 544,076

7 Claims. (Cl. 260-39145) This invention is concerned generally with novel steroid compounds and processes of preparing them. More particularly, it relates to A -3,20-diket0-11,17- dihydroxy-Zl-oxygenated-pregnadiene compounds, and with processes for preparing these novel A -3,20- dilteto-l 1,l7-dihydroxy-21-oxygenated-pregnadiene compounds. These new compounds possess pharmacological activity similar to that shown by cortisone and are thus of value in the treatment of arthritis and related diseases. Moreover, in addition to possessing cortisone-activity, these A -3,20-diketo-l1,17-dihydroxy-2l-oxygenatedpregnadienes differ from cortisone in being relatively free from undesired side effects such as sodium or Water retention action.

This application is a division of co-pending application Serial No. 483,858, filed January 25, 1955.

These A -3,20-diketo 11,17 dihydroxy-Zl-oxygenated-pregnadiene compounds, subject of the present invention, may be chemically represented as follows:

CHrOR l----on wherein R is hydrogen or an acyl radical.

The d -3,20 diketo 11,17 dihydroxy-Zl-oxygenated-pregnadienes are conveniently prepared starting with the known 9-bromo-cortisone. The 9-bromo-cortisone is reacted with a dehydrohalogenating agent such as collidine to produce A -3,11,ZO-triketo-17,21-dihydroxypregnadiene which is reacted with semicarbazide to form the corresponding 3,20-bis-semicarbazone which, upon reaction with an alkali metal borohydride, such as sodium borohydride in aqueous tetrahydrofuran, is converted to A -3,20-diketo-11,17,2l-trihydroxy-pregnadiene 3,20-bis-semicarbazone. The latter compound is then reacted with an aqueous mineral acid solution in contact with a water-immiscible solvent such as chloroform to produce A -3,20-diketo-11,17,21-trihydroxypregnadiene, which is reacted with an acylating agent as for example a lower alkanoic anhydride, such as acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride, and the like, in the presence of a tertiary amine such as pyridine to form A -3,20--diketo-11,17- di'nydroxy-Zl-acyloxy-pregnadiene as for example A 3,20-diketo 11,17 dihydroxy 21 aeetoxy-pregnadiene, A -3,20-diketo 11,17 dihydroxy-21-propionoxy-pregnadiene, A -3 ,20-diketo-1 1,17-dihydroxy-2 l-butyroxypregnadiene, A -3,20-diketo-1 1,17-dihydroxy-2l-benzoxy-pregnadiene, and the like.

The following example illustrates a method of carrying out the present invention but it is to be understood that this example is given for purposes of illustration and not of limitation.

Example 1 A solution of 3 parts of A -9-bromo-3,11,20-triketo- 17,2l-dihydroxy-pregnene (9-bromo-cortisone) in 50 parts of collidine is heated for one hour under reflux, and the collidine is evaporated in vacuo. The residual material is dissolved in chloroform, and the chloroform extract is Washed with dilute aqueous hydrochloric acid, then with water, dried, and evaporated to dryness in vacuo. The residual material is purified by chromatography followed by recrystallization from ethyl acetate to give A -3,11,20-triketo 17,21 dihydroxy-pregnadiene.

A mixture of 0.5 part of A -3,1l,20-triketo-l7,2l dihydroxy-pregnadiene, 0.5 parts of anhydrous sodium acetate, 0.62 part of semicarbazide hydrochloride and 35 parts of 95% ethanol is heated at a temperature of about C. for about 3 hours. The reaction mixture is evaporated to small volume in vacuo, the concentrated solution is diluted with water, and the insoluble material which precipitates is recovered by filtration, washed with water and dried. The resulting material is purified by chromatography followed by recrystallization from alcohol to give A 3,11,20 triketo 17,21 dihydroxypregnadiene 3,20-bis-semicarbazone.

To a suspension of 0.2 part of lithium borohydride in 10 parts of anhydrous tetrahydrofuran is added, dropwise with stirring over a 30-minute period, a solution of 0.44 part of A -3,1l,20-triketo 17,21 dihydroxy-pregnadiene 3,20-bis-semicarbazone in 2.5 parts of dimethylformamide and 5 parts of tetrahydrofuran, while maintaining the reaction mixture at a temperature of about 25 C. The resulting mixture is stirred for an additional 40 minutes at 25 C., 20 parts of a 10% aqueous solution of acetic acid is added cautiously to the mixture thereby decomposing excess lithium borohydride. The clear solution is evaporated in vacuo nearly to dryness, the residual material is slurried with 10 parts of Water, and the insoluble material is recovered by filtration, Washed with water, and dried to give A -3,20-diketol l,17,21trihydroxy-pregnadiene 3,20-bis-semicarbazone.

A mixture of 0.3 parts of A -3,20diketo-11,17,21- trihydroxy-pregnadiene 3,20-bis-semicarbazone, 5 parts of glacial acetic acid, 1.5 parts of water, 0.85 parts of sodium acetate, and 0.8 parts of 90% aqueous pyruvic acid is heated under nitrogen for 4 hours at about C. The reaction mixture is diluted with 20 parts of water, and the aqueous mixture is evaporated nearly to dryness in vacuo. The residual material is slurried with water, and the organic material is extracted with ethyl acetate. The ethyl acetate solution is washed until neutral, dried, decolorized, and evaporated to dryness. The residual material is purified by chromatography followed by recrystallization from ethyl acetate-ether to give A 3,20-diketo 11,17,21 trihydroxy-pregnadiene. The latter material is reacted with an excess of acetic anhydride in pyridine at room temperature for a period'of about 15 hours, and the crude acetylated product is purified by chromatography followed by recrystallization from ethyl acetate to give substantially pure A -3,20-diketo-l1,17- dihydroxy-Zl-acetoxy-pregnadiene.

Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of this invention.

3 I claim: L. Ai 3,20-diketo-hl,l.7-dihydroxy-21-0xygenatedpregnadiene having the following formula:

CH2OR wherein R is a substituent selected from the group which consists of hydrogen and lower hydrocarbon carbonyl substituents.

2. A -3,20-diket0-1'1fi,17ot,2 l-trihydroxy pregnadiene.

3. A -3,20diket0-11,17-dihyclroxy-2l-lower hydrocarbon carbonyloxy-pregnadiene.

4. A -3,20 diketo 11e,'17a-dihydroxy-2l-acetoxypregnadiene.

5. A -3,20-diketo 11fi,17oc dihydroxy-Zl-benzoxypregnadiene.

6. The process which comprises reacting M -3,11,20- triketo-17,2l-dihydroxy-pregnadiene with semicarbazide to form the 3,20-bis-semicarbazone, reacting this 3,20- bis-semicarbazone with an alkali borohydride to form A -3,20-diketo-11,17,2l-trihydroxy-pregnadiene 3,20-

bis-semicarbazone, reacting the latter compound with a hydrolyzing agent to produce A -3,20-diketo-l1,17,21- trihydroXy-pregnadiene, and reacting this M -3,20- diketo-ll,17,2l-trihydroxy-pregnadiene with a lower hydrocarbon carboxylic acylating agent thereby forming A 9 -3,2O-diketo-11,17-dihydroxy-2l-lower hydrocarbon carbonyloxy-pregnadiene.

7. The process which comprises reacting A -3,11,20- triketo-l7a,2l-dihydroxy-pregnadiene with semicarbazide to form A -3',11,20-triketo-l7u,2l-dihydroxy-pregnadiene 3,20-bis-sernicarbazone, reacting this 3,20-bis-semicarbazone with lithium borohydride to form A -3,20- diketo 11p,17u,2l-trihydroxy-pregnadiene 3,20-bis-semicarbazone, reacting this compound with a mixture of dilute aqueous hydrochloric acid and chloroform to produce A -3,20 diketo 11 8,17a,21-trihydroxy-pregnadiene, and reacting the latter compound with acetic anhydride thereby forming A -3,2O-diketo-11p,l7a-dihydroxy-Zl-acetoxy-pregnadiene.

References Cited in the file of this patent UNITED STATES PATENTS 2,409,798 Reichstein Oct. 22, 1946 2,734,897 Chemerda Feb. 14, 1956 2,740,797 L-aubach Apr. 3, 1956 FOREIGN PATENTS 1,052,936 France Sept. 30, 1953 

1. $4,8(9) -3,20-DIKETO-11,17-DIHYDROXY-21-OXYGENATEDPREGNADIENE HAVING THE FOLLOWING FORMULA: 